Schizophrenia is a type of disease characterized in severely schizophrenic cognition and emotion, presenting as the influence on the basic behavior of a human, such as language, thinking, feeling, self-perception or the like. This disease encompasses a large variety of disorders, such as those involved in psyche, e.g. delusion, paranoia, illusion or the like. Schizophrenia is the most serious mental disease. About 1% of the people all over the world suffer from schizophrenia, and only 5% of them can be cured after treatments. In addition, schizophrenia is always accompanied with various complications, e.g. anxiety, depression, psychic drug abuse or the like. It was shown in a study by Datamonitor that over ⅓ of the patients with schizophrenia suffer from one or more complicated psychoses or cognitive disorders.
The anti-psychosis drug exerting its pharmacological action by blocking dopamine D2 receptor is conventionally known as the 1st generation anti-psychosis drug, i.e. the “typical” anti-psychosis drug (e.g. haloperidol). This drug is effective for positive symptoms of schizophrenia, but not effective for negative symptoms and cognitive disorders. Furthermore, the typical anti-psychosis drug generally has serious EPS (extrapyramidal system) side effects and is not effective for ⅓ of the patients with schizophrenia.
A series of new anti-psychosis drugs have been developed since 1960s, including ziprasidone, risperidone or the like, which are considered as the 2nd generation anti-psychosis drugs (the novel anti-psychosis drug). Although these drugs have different pharmacological actions, they share the same pharmacological properties, i.e. the affinities for 5-hydroxytryptamine (5-HT) receptor (5-HT1A, 2A, 2C) and noradrenalin (NA) receptor (α1, α2) are much higher than those for D2 receptor, resulting in the decrease of the ratio of D2/5-HT2A. Their clinical effects are more advantageous over those of the 1st generation anti-psychosis drugs, since they are effective for the positive symptoms like the conventional anti-psychosis drug, and are effective for the negative symptoms and cognitive defect symptoms and have broader application spectrum. However, these drugs have the side effects of extended QT interval, hyperprolactinemia, weight gain or the like. Therefore, it is needed to find a new drug, which is effective for schizophrenia positive and negative symptoms and cognitive disorders, and has less side effects.
Aripiprazole belongs to a butyl benzene prazosin compound, which was approved by FDA in November, 2002. This drug has a particular action mechanism as having high affinities with dopamine D2, D3, 5-HT1A and 5-HT2A receptors, and medium affinities with D4, 5-HT2C, 5-HT7, α1, H1 receptors and 5-HT reuptake site. Aripiprazole exerts its effect against schizophrenia through its partial agonistic action for D2 and 5-HT1A receptors and antagonistic action for 5-HT2A receptor, and has the effect of stabilizing dopamine systemic activity. Clinical trials have shown that aripiprazole is effective for both the positive and negative symptoms of schizophrenia, and its long-term application can reduce the reoccurrence of schizophrenia, and improve disorders of emotion and cognitive function. Moreover, its EPS side effects and the effect of increasing serum prolactin level are less than those of the conventional anti-psychosis drug or the above non-typical anti-psychosis drug.
5-hydroxytryptamine system plays an important role in modulating the function of prefrontal cortex (PFC), including emotion control, cognitive behavior and working memory. The pyramidal neurons and GABA interneurons of PFC contain several 5-hydroxytryptamine receptor subtypes 5-HT1A and 5-HT2A with high density. It has been shown recently that PFC and NMDA receptor pathway are the targets of 5-HT1AR, and these two receptors modulate the excitatory neuron of cerebral cortex, thereby affecting the cognitive function. In fact, various preclinical data have shown that 5-HT1AR may be the new target of the development of anti-psychosis drug. The high affinity of non-typical anti-psychosis drug (e.g. olanzapine, aripiprazole or the like) to 5-HT1AR and its low EPS side effects indicate that 5-hydroxytryptamine system plays an important role in modulating the function of prefrontal cortex (PFC), including emotion control, cognitive behavior and working memory. Pyramidal neurons of PFC and GABA interneurons contain several subtypes of 5-hydroxytryptamine receptors including 5-HT1A and 5-HT2A with especially high density. It has been shown recently that 5-HT1A agonist is associated with non-typical anti-psychosis drug therapy, which can improve negative symptoms and cognitive disorders. In the treatment of schizophrenia with the non-typical anti-psychosis drug clozapine, it was found that 5-HT2A plays an important role in various aspects, including cognition, emotion regulation and motion control. The blocking of 5-HT2A receptor can normalize the release of dopamine, exerting the effect of anti-psychosis. In addition, 5-HT2C receptor is closely related with weight gain.
The distribution of D3 receptor in brain mainly locates specifically at limbic system and there are two major DA neural pathways in brain: one is nigrostriatal pathway regulating the motion function, while the other is mesencephalic ventral tegmental area-accumbens nucleus-prefrontal cortex DA pathway, which is closely associated with learning cognition and emotion behavior, and its disorder will lead to schizophrenia. This DA pathway is the main pathway of reward effect in brain. D3R is distributed in both of the DA neural pathways, and has complex interaction with other DA receptor subtypes, and thus may be the target of anti-psychosis drug therapy. Antagonism of selective D3 receptor can reduce the negative and cognitive symptoms of schizophrenia, which can additionally prevent extrapyramidal system side effects, including tardive dyskinesia, Parkinson's disease or the like.
Therefore, it is important for clinical treatment to find novel anti-schizophrenia drug which can bind to multiple receptors and has less side effects.